(1) Field of the Invention
The present invention relates to pharmaceutical substance-containing microcapsules and a process for the preparation of the same.
(2) Brief Description of the Prior Art
As the conventional microencapsulation process for microencapsulating a pharmaceutical substance insoluble in cyclohexane, such as aspirin, with ethyl cellulose, a process is known in which butyl rubber or polyethylene is used as a phase separation inducing agent and is dissolved by heating into a cyclohexane solution containing ethyl cellulose, a powder of a pharmaceutical substance is dispersed in the solution and the dispersion is cooled to cause phase separation and form pharmaceutical substance-containing microcapsules (see Japanese Patent Publication No. 528/67 and Japanese Patent Publication No. 11399/69). According to this known process, however, it is impossible to increase the wall thickness beyond a certain level in resulting capsules, and therefore, a sufficient effect of retarding release of the pharmaceutical ingredient cannot be attained.
As an improvement of the above-mentioned conventional process, there has been proposed a process in which microcapsules prepared according to the above-mentioned process are further treated with paraffin to form a double-wall structure (see British Pat. No. 1,117,270). This Process, however, has disadvantages in that the steps for forming microcapsules are complicated and it is very difficult to remove the solvent used sufficiently from the capsule wall. Further, no satisfactory effect of retarding release of the pharmaceutical ingredient can be attained.
As a result of investigations, we previously proposed a process for microencapsulating a pharmaceutical substance with ethyl cellulose by liquid-liquid phase separation, wherein polyisobutylene having an average moleculr weight of 8,700 to 135,000 or its mixture with butyl rubber having an unsaturation degree of 0.7 to 3.0 mole % is used as the phase separation inducing agent (see Japanese Patent Publication No. 30136/75). According to this process, the wall thickness can be adjusted within a range of from a thickness providing a semipermeable membrane wall to a thickness providing an impermeable membrane wall, and therefore, microcapsules having a quick releasing property or a gradual releasing property can optionally be prepared. However, according to this process, in order to retard release of the pharmaceutical ingredient, it is necessary to increase the wall thickness of microcapsules. Increase of the wall thickness of microcapsules naturally results in dilution of the pharmaceutical ingredient as a core. Accordingly, incorporation ratios of an excipient, a disintegrating agent, a binder and a lubricating agent to be used for formation of powders, granules, fine particles, tablets and capsules are drastically limited, and formulation of medicaments becomes very difficult. Further, if the wall thickness is increased, the deviation of the speed of release of the pharmaceutical ingredient becomes large, and in some case, the pharmaceutical ingredient cannot completely be released. Furthermore, when such microcapsules are mixed the other ingredient, the amount of said other component adsorbed in the capsule wall is increased and the quality of the resulting medicine is degraded. It has been found that these disadvantages are involved in the previously proposed process.